The present invention provides novel compositions of matter and processes for their preparation. Particularly, the present invention relates to novel chemical intermediates and associated processes for the preparation of both known and novel precursors of khellin and other furochromone analogues, which have demonstrated lipid-altering and antiatherosclerotic activity. See. U.S. Pat. No. 4,284,569. Furthermore, these chenmical intermediates can be used in the preparation of certain benzofurans and benzothiophenes which have been shown to inhibit the synthesis of leukotrienes and/or inhibit the action of lipoxygenase in mammalian metabolism. See application, Ser. No. 561,601, filed Dec. 14, 1983 now abandoned. The synthesis of the compounds, which are noted herein as D-3 and D-4 is shown herein in Chart D.
Khellin and related compounds are known to exert a wide variety of pharmacological effects. Khellin has been reported to exhibit useful antiatherosclerotic activities. Moreover, numerous analogues of khellin likewise are known to exert useful antiatherosclerotic effects. For example, 7-methylthiomethyl-4,9-dimethoxyfurochromone is described in U.S. Pat. No. 4,284,569 as such a useful antiatherosclerotic substance.
The leukotrienes are a class of unsaturated fatty acid compounds which are derived from arachidonic acid by the action of lipoxygenase. See, e.g., Samuelsson, Trends in Pharmacological Sciences 5:227 (1980); Samuelsson et al., Annu. Rev. Biochem. 47:997-1029 (1979). For a discussion of leukotriene nomenclature, see Samuelsson et al., Prostaglandins 19:645 (1980).
The leukotrienes have been discovered as potent constrictors of human bronchi. That is, certain leukotrienes are mediators of the action of slow-reacting substance of anaphylaxis (SRS-A). See, e.g., Dahlen, Nature 288:484 (1980). These compounds are therefore important mediators of bronchoconstriction in humans.
The role of leukotrienes as agonists in immediate hypersensitivity and other pathological conditions has led to research into inhibitors of leukotriene biosynthesis and leukotriene antagonists. See, e.g., Corey et al., Tet. Lett. 21:4243 (1980).
Im mammalian metabolism, arachidonic acid is transformed to 12-L-hydroperoxy-5,8,10,14-eicosatetraenoic acid by the action of 12-lipoxgenase. See Hamberg et al., Proc. Nat. Acad. Sci. 71:3400-3404 (1974). Similarly, 5-lipoxygenase transforms arachidonic acid into 5-S-hydroperoxy-6,8,11,14-eicosatetraenoic acid. Thus, an agent which inhibits the action of lipoxygenase would be useful in treating or preventing untoward conditions associated with lipoxygenase products.
Therefore, compounds which inhibit the action of lipoxygenase are useful in the treatment of inflammatory conditions where it is desirable to prevent migration of polymorphonuclear leukocytes to the inflammatory site. They are also useful in the treatment of asthma.
Methods for the total synthesis of khellin and related compounds are known. For example, pyrogallol has been employed as a starting material for the synthesis of furochromones such as khellin. See J. R. Clarke et al., J. Chem. Soc. 302 (1949), R. A. Baxter et al., J. Chem. Soc. S30 (1949), A. Schonberg et al., J. Am. Chem. Soc., 73:2960 (1951), V. V. S. Murti et al., Proc. of the Indian Acad. of Sci. 30A:107 (1949), and T. A. Geissman et al., J. Am. Chem. Soc. 73:1280 (1951). Also descriptive of the synthesis of khellin are E. Spath et al., Chem. Ber. 71:106 (1938), O. Dann et al., Chem. Ber. 93:2829 (1960), O. Dann et al., Ann. Chem. 605:146 (1957), and V. V. S. Murti et al., J. Sci. Ind. Res. (India) 8B:112 (1949). See also U.S. Pat. No. 2,680,119 describing the synthesis of khellin and related compounds.
Other references describing the synthesis of intermediates useful in the preparation of khellin for analogues include: R. Aneja et al., Chem. Ber. 93:297 (1960), R. Aneja et al., J. Sci. Ind. Res. (India) 17B:382 (1958), T. S. Gardner et al., J. Org. Chem. 15:841 (1950), and L. R. Row et al., Indian J. Chem. 5:105 (1967).
Accordingly, the references cited above describe the preparation of 1-(6-hydroxy-4,7-dimethoxy-5-benzofuranyl)-ethanone. Also known is the related compound 6-hydroxy-4,7-dimethoxy-5-benzofurancarboxylic acid, methyl ester, described by C. Musante Gazz. Chim. Ital. 88:910 (1958).
One method for the preparation of the lipoxygenase and/or leukotriene-inhibiting benzofurans and benzothiophenes is described in said application, Ser. No. 561,601, filed Dec. 14, 1983.